TIR-199

**TIR-199** is a syrbactin-class irreversible proteasome inhibitor derived from the plant virulence factor syringolin A of *Pseudomonas syringae pv. syringae*. It potently and selectively inhibits the chymotrypsin-like (CT-L/β5), trypsin-like (T-L/β2), and caspase-like (C-L/β1) activities of the constitutive proteasome and immunoproteasome, with Ki50 values in the low nanomolar range (e.g., 14-55 nM for CT-L in MM cell lines), outperforming bortezomib in resistant cells due to a low resistance index (1.7-2.2). TIR-199 induces apoptosis in bortezomib-resistant multiple myeloma (MM), mantle cell lymphoma (MCL), triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and neuroblastoma cells, accumulates proteasome substrates (e.g., p62, IκBα, p21), and shows specificity without inhibiting 50 other proteases *in vitro*. It demonstrates *in vivo* efficacy in MM xenograft models by reducing tumor burden, extending survival, and delaying bone degeneration at doses of 5-25 mg/kg intraperitoneally, warranting further development as a next-generation proteasome inhibitor to address chemoresistance.[1][2][4]